abc

1. • Drug resistance mechanisms in Mycobacterium TB
started if there is Inhalation of Mtb.
• Phagocytosis of bacilli
• Inflammatory cell recruitment
AM secreted IL-12 and IL-18
IFN-γ induce bacterial killing
TNF-α is essential in the control of Mtb growth and
granuloma formation
• Control of mycobacteria growth
• Stops Mtb proliferation
• Chronic cytokine stimulation
• Granuloma is formed by several cells recruited to
• the lung. Inside, infected macrophages contain the
Mtb preventing their spread.
• Postprimary tuberculosis
Mycobacteria persistence
is associated to a failurein
the immune-surveillance
• Disease may reactivate
• Damage of nearby
bronchi
• Spreading of the Mtb to
other areas ofthe lung

2. • The primary step to treat drug resistance in Mycobacterium is to
understand the mechanisms involved in antibiotic resistance
Primary resistance results from infection with a drug-resistant strain,
whereas resistance that develops during therapy is referred to as
secondary or acquired resistance.
• Failure in TB treatment due to Drug resistance mechanisms in
Mycobacterium both Intrinsic drug resistance (newly acquired
mutations) antibiotic resistance and Acquired drug resistance
1. Acquired drug resistance
drug resistance in Mtb primarily emerges due to mutations in chromosome,
genes encoding drug targets or drug-activating enzymes, in response to
selection pressure of antibiotics

3. 2. Intrinsic drug resistance
The following are the mechanisms contributing to the overall intrinsic drug resistance in Mtb
1 Impermeability of cell envelope
• Mycobacterial cell envelope subdivides it into three distinct entities namely outermost
layer called capsule, cell wall and cell membrane. The periplasmic space separating the
cell wall from the membrane lipid bilayer protects the cells from environmental
stresses and acts as permeability barrier for antibiotics Furthermore, presence of
wide array of lipids makes the Mtb cell envelope extremely thick, highly
hydrophobic and hinders the diffusion of even hydropho bic molecules, which
include antibiotics such as rifamycins, macrolides, fluoroquinolones
2 Drug efflux
Drug efflflux pump proteins constitute an active efflux mechanism which expels
the drug molecules entering the bacterial cell. Upon exposure to isoniazid and
rifampicin, overexpression of Rv1258c was found in clinical MDR-TB isolates.
Furthermore, point mutations (V219A and S292L) were identifified in efflflux
pump Rv1258c and in conferring drug resistance in clinical isolates to multiple
drugs including isoniazid, pyrazinamide and streptomycin

4. 3 Drug degradation and modification
• Several enzymes produced by Mtb have evolved to modify or
degrade different classes of antibiotics.Bacterial
transpeptidases are enzymes involved in Peptidoglikan cross-
linking and thus, essential for cell wall synthesis.
4. drug target modification
• drug target modification which can prevent binding of antibiotic to
target site. These drugs reversibly bind to a specifific site within
50S subunit of bacterial ribosomal RNA and prevent
translocation of peptidyl-tRNA, thus inhibiting protein synthesis
and mycobacterial growth

5. • There are 6 categori of drTb Monoresistance: is caused by M. tb strains that are
resistant to one of antiTB drugs ex:isoniazid
• Polyresistance: is caused by M. tb strains that are resistant to more one of other
antiTB drugs (neither Rifampicinn nor Isoniazid)
• Rifampicin-resistant TB (RR-TB) is caused by M.Tb strains that are resistant to
rifampicin. RR-TB strains may be susceptible to isoniazid or resistant to it (i.e. MDR-TB),
or resistant to other first line or second-line TB medicines.
• Multidrug-resistant TB (MDR-TB) is caused by M. Tb strains that are resistant to at least
both isoniazid and rifampicin.
• Pre-XDR-TB defined as ‘MDR-TB with additional resistance to either a fluoroquinolone or
a second-line injectable drug’
• Extensively drug-resistant TB (XDR-TB) is TB that is resistant to any
fluoroquinolone and to at least one of three second-line injectable drugs (capreomycin,
kanamycin and amikacin), in addition to multidrug resistance.
• Totally DRTB has been used in the literature to refer to strains of M tuberculosis that show
in-vitro resistance to all medications that are available for Testing

6. • In high burden country the rate of DRTB is higher than low burden
country
• Most people that were diagnosed with DR-TB had a history of having received treatment for TB.
• risk factors include close contact to a patient with MDR-TB, migration,
HIV infection and young age
• and previous TB treatment in the development of drug resistant TB infection.
• the development of DR-TB in Abusers of alcohol might be associated with
its substantial role in failure rate among new TB cases.
• Very recently, WHO concluded that people living with HIV are facing the
emerging threats of drug resistant TB.
Risk factors for DRTB

7. Tb infection occur whenThe inhalation of at least one viable and
virulent M.Tb droplet nucleus must reach the alveolar macrophages
within the lung. And its depend on Cough strength and frequency, -
Presence of lung cavities, - Sputum viscosity -Ventilation, frequency and
duration of contact. When hypertramission in prolonged
hospitalization, delayed diagnosis of drug resistance and poor
ventilation
From animal studi A cut-off time of 8 h for exposure, and need 12 to 18
month of contacts with The number of infectious doses was 340 m3 of
air are leading to effective TB transmission

8. • Patients , Health staff and visitors are factors favour disease transmission.
• The sources of transmission in hospitals can involve to Hypertransmitions if
Undetected, - Untreated TB - Patients with known TB, but unknown drug
resistance (receiving ineffective therapy)
• The important questions is Who is infectious?
Patient TB is still infectious When not treated with effective treatment, acid
fast bacilli Smear and culture did not convert and there are no clinical and
radiological improvement.
Smear sputum M.Tb positive more infectious than smear sputum M.Tb
negative whether culture M.Tb positive or negative
Contacts of patients with multidrug resistant tuberculosis were at higher risk
of tb infection than contacts exposed to drug sensitive tuberculosis

9. • DRTB Therapy consist of 2 regimen Standar regimen and
individualized
• the decision to use the newer WHO-recommended short course
versus individualized regimen in selected patients will be
dependent on several factors, including previous treatment,
local resistance profiles, patient acceptance, and the
requirement for proven or highly likely fluoroquinolone and
aminoglycoside isolate susceptibility, and absence of probable
or proven resistance to any of the components of the regimen
(except isoniazid)68 •
• What ever the duration of the regimen used, psychosocial and
financial support are crucial elements to maintain adherence •
Patients should be monitored for adverse drug reactions

10. Treatment outcome definitions for DRTB
• Died A TB patient who dies for any reason before starting or during the course of
treatment.
Lost to follow-upA TB patient who did not start treatment or whose treatment was
interrupted for 2 consecutive months or more.
Treatment failureLack of conversion by the end of the intensive phasea , or bacteriological
reversion in the continuation phase after conversion to negative, or evidence of additional
acquired resistance to fluoroquinolones or second-line injectable drugs, or adverse drug
reactions (ADRs)

11. • Cured Treatment completed as recommended by the national policy
without evidence of failure and three or more consecutive cultures taken
at least 30 days apart are culture negative after the intensive phase.
However, recurrences after treatment completion would need to
differentiate between relapse (disease caused by the same strain) and re-
infection caused by a different strain.
• The definition of relapse and reinfection was based on comparison of M.
tuberculosis DNA fingerprint patterns using RFLP restriction fragment
length polymorphismanalysis . More advanced methods such as Whole
Genome Sequencing (WGS) may be more powerful to discriminate
different strains.

12. the management of DR-TB patients remains highly challenging
due to the psyhosocial issues
• The long duration of DRTB treatment increase poor adherence
• Side effect : prolong QT from bedaquline an fluoroquinolone, side
effects (depression, convulsions, consciousness, psychosis, suicide; ),
especially due to the cycloserine. Major adverse events related to
linezolid include anaemia, peripheral neuropathy, gastrointestinal
disorders, optic neuritis and thrombocytopenia.
• Stigma in the context of MDR-TB negatively impacts the patient
in accessing healthcare facilities.The impact of stigma reported
has led to divorce, cancellation of impending marriages,
breakdown of family relationships and also isolation within the
family

13. • Inability to work due to the side effects of the drugs and therefore
loss of income has been a major impediment leading to treatment
default.
• Because of these barrier most of patient experiented Treatment
faulire and psychological distress and the status remain infectious so
the patient cannot return to work

14. • Monitoring therapy for DRTB patients
• - Clinical,
• - Laboratory
• - Microbiology and
• - Radiology.
• WHO guidelines suggest monthly sputum smear microscopy and
• culture as an adjunct to clinical monitoring of patients to assess treatment
outcome.
• in DRTB patient Modest specificity and the best maximum combined
sensitivity and
• specificity occurred between month 6 and month 10 of treatment

15. .
In a situation of failure (e.g. when
- Smear and culture do not convert, Initial response with subsequent culture
reversion,
- The need for a regimen change because of adverse events or acquired drug
resistance (the treatment is not effective).
- Clinical and radiological indicators deteriorate
the patient is likely to be still infectious.
Colony numbers (in smear cultures) and time or cycles to positivity in molecular
detection can also be used to assess the treatment response in clinical trials, but not
for assessing infectiousness unless providing evidence of treatment failure

16. • A TB patient should be discharged from hospital if:
• There is no continuing clinical need for inpatient treatment
• Clinical improvement is observed after administration of effective therapy
• Effective treatment has been ensured
• and continuity of care and DOT have been ensured in outpatient, home or
community settings.
• Effective treatment of TB can rapidly render patients noninfectious, long before
conversion of sputum acid-fast smear or culture to negative occurs The median
time to convert sputum culture to a negative result was 38.5 days
• positive smear is not a contraindication for hospital discharge.

17. HOSPITAL DISCHARGE CRITERIA
• Confirmed MDR-TB Prior to discharge from the hospital, continuation
of care and monitoring during the outpatient phase of treatment
must be ensured.
If patient
• Unable to produce sputum
• Overall symptoms have improved
Discharge decisions should be taken by a multidisciplinary team

18. Criteria for hospital admission
• A proportion of cases still need to be admitted for medical reasons,
including
• Severe cases,
• Life threatening conditions,
• Comorbidities,
• Psychiatric problems,
• Adverse drug reactions and,
• For social reasons

19. Occupational risk for TB infection

20. • The rate of diagnosis of active TB in HCWs has consistently been
reported to be higher than that for the general population in a
number of studies conducted in countries with low and high TB
prevalence
• HCWs globally are at increased risk for TB infection and disease, although
rates of occupationally acquired TB are highest in low and middle-income
countries , In these settings, drug-resistant TB (DR-TB) also affects HCWs
at a greater frequency than the communities they serve.
• Clinical staff (nurses and doctors) appear to be at highest risk

21. TB among HCWs leads to :
- Worker absenteism,
- Disruption of health services, - Loss
of productivity.

22. Return to work Criteria for DR TB patients
• 1. Have had three negative AFB sputum smear results collected 8–24
hours apart (at least one of which should be an early morning
specimen)
• 2. Have responded to anti-TB treatment that should be effective
based on drug susceptibility testing results
• The assessment of whether TB patient is no longer infectious and can
return to work should be made by a physician who has expertise in
the management of TB.
• Return to work will be linked to medical certification that the
employee is no longer infectious and is not otherwise ill or
incapacitated for his or her usual work.

23. Patients with pulmonary DR TB can be considered non-infectious when:
1. They have received adequate chemotherapy for two to three weeks;
2. They show clinical improvement; and
3. There is a negligible chance of MDR-TB
• Dharmadhikari et al. and Finenelly et al concluded that the standard
MDR-TB treatment used in South Africa rapidly and effectively
suppresses MDR-TB disease transmission, regardless of the sputum
smear and culture status
• rapid fall in infectiousness of patients after starting treatment,
Loudon theorized that evaporation of the droplet nuclei could
increase the drug concentration around bacilli
• This mechanism might inactivate the bacilli or hamper their capacity
to successfully infect human hosts. Although the drug concentration
must increase as droplets evaporate, this phenomenon was never
confirmed experimentally to reduce the transmission rate.

24. • The definition of relapse and reinfection was based on comparison of
M. tuberculosis DNA
• fingerprint patterns using RFLP analysis – state of the art method at
the time this study was
• conducted. More advanced methods such as Whole Genome
Sequencing (WGS) may be
• more powerful to discriminate different strains. However, using WGS
was beyond the scope
• of our study

25. Mycobacterium tuberculosis as Biohazards
Precautions against airborne infection transmission are necessary because
biohazards, such as the Mycobacterium tuberculosis that causes TB, are
transmitted by airborne droplets.
WHO suggests that people deemed to be at a low risk of RR-TB and /MDR-
TB should be placed in single rooms and that those at a high risk should
ideally be accommodated in a negative-pressure room while rapid
diagnostic tests are urgently performed until effective treatment starts
Precautions against airborne infection transmission are necessary
because biohazards, such as the Mycobacterium tuberculosis that
causes TB, are transmitted by airborne droplets.
WHO suggests that people deemed to be at a low risk of RR-TB and
/MDR-TB should be placed in single rooms and that those at a high
risk should ideally be accommodated in a negative-pressure room
while rapid diagnostic tests are urgently performed until effective
treatment starts

26. Administrative controls
International Labour Office Health WISE Action Manual. 2014;1
• Control the spread of pathogens by using cough etiquette
• Reduce the time a person stays in a health facility and treat promptly those
infected
• Identify promptly and early people with TB symptoms, quarantinee infectious
patients.
• Train health workers TB signs, symptoms, prevention, treatment, and
infection control.

27. International Labour Office Health WISE Action Manual. 2014;1
Environmental
controls

28. CONCLUSION